Binuclear platinum complexes, method for preparing same and pharmaceutical compositions containing said complexes

ABSTRACT

A family of platinum complexes which are stable and exhibit anticancer activity.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a new class of dinuclear platinumcomplexes. It also relates to a process for their preparation. Theinvention further relates to the pharmaceutical compositions containingthem and to their use for the therapeutic treatment of various cancers.

2. Description of the Background

Cisplatin and oxaliplatin are known cytostatic antineoplastic agents,which are advantageously used in the therapeutic treatment of variouscancers.

Cisplatin is prescribed in particular for treating cancers of thetesticles, of the ovaries, epidermoid cancers, for treating tumors ofthe head, of the neck, etc.

Oxaliplatin is prescribed for treating the same type of cancers, moreparticularly cancers of the ovaries, as well as cancers of the colon, ofthe upper respiratory tracts and epidermoid cancers.

Each one of these antineoplastic agents has its own specificity and, asa result, as a function of the stage of evolution of the disease, of thepatient's condition or of the type of cancer to be treated, thepractitioner may be led to prescribe either one of said agents. Incertain cases however, the sought therapeutic effect is not reached orat least its maximum level is not reached.

Like other cytostatic antineoplastic agents, in particular otherorganometallic derivatives of platinum, cisplatin and oxaliplatin havean intrinsic toxicity which constitutes a serious limiting factor whichthe practitioner has to take into account in the prescribed treatment.In particular, cisplatin has a rather significant renal and neuromotivetoxicity, all the more so as said toxicity has proved to be cumulative.It also provokes strong vomiting and can cause bradycardia, as well asmyelosuppression. To a lesser degree, oxaliplatin causes a reversiblesensorial dysesthesia, the effects of which can be easily reduced bysuitably modulating the dose administered to the patient. But the resultis that the practitioner is therapeutically limited particularly as faras curing means are concerned.

Oxaliplatin belongs to the class ofplatinum(II)-trans-1,2-diaminocyclohexane complexes which are currentlyin full development. Said complexes, or "dach" complexes are beingclinically tested in Europe, and in particular in France, as well as inthe United States and Japan and they are especially efficient againstmelanomae and tumors of the ovaries, of the uterus, of the stomach andof the intestine, etc.

U.S. Pat. No. 4,169,846 describes such complexes, namely cisplatin(II)complexes and complexes of 1,2-diaminocyclohexane, in particular the[Pt(II)-oxalato (1R),(2R)-diaminocyclohexane] complex which is thecompound known under the designation of oxaliplatin.

When said "dach" complexes are combined with 5-fluorouracile (5FU), theyare particularly efficient for treating cancers of the stomach.

And when they are combined with the 5-fluorouracile and folinic acid,the "dach" complexes are especially useful for treating cancers of thecolon.

Patent EP-A-143 478 relates to a method of administration of cisplatinin the form of an acid aqueous solution, and more specifically anhydrochloric acid solution having a pH preferably comprised between 3.2and 3.5 and containing chloride ions for example from sodium chloridefor stabilizing the solution and thus avoiding hydrolysis.

U.S. Pat. No. 4,177,263 which also relates to cisplatin, describes amethod for treating cancer tumors in animals, which method consists ininjecting by parenteral route a complex platinum agent in an efficientquantity for causing regression of the tumor.

Clinical tests conducted in France on the use of the combination ofoxaliplatin with cisplatin have shown the remarkable effect of suchcombination on the cancer of the liver. However, it has been found thatthere are problems of stability with the combined complexes.

International patent application WO 94/12193 describes in particular acomposition intended for the joint administration of cisplatin andoxaliplatin as a combination after extemporaneous reconstitution byaddition of aqueous liquid in the form of a lyophilisate containing thecisplatin and the oxaliplatin in a weight ratio comprised between 2:1and 1:2.

SUMMARY OF THE INVENTION

A new family of platinum complexes has now been found, which complexesare very stable and have an anticancer activity.

The new complexes of the invention have one of the general formulae (I)or (II): ##STR1## in which: Y--Y is an amine bidentate ligand of formula

NH₂ --R₁ --NH₂ in which R₁ is a C₂ -C₆ linear or branched alkylene groupor an o-phenylene group;

or a group of formula ##STR2## in which n=2, 3, 4, 5 m=0, 1,

and I=0, 1;

A₁ and A₂ represent either two ammine identical monodentate ligands,n-isopropylamine or (C₃ -C₇) cycloalkylamine, or they are bondedtogether and form an amine bidentate ligand of formula:

NH₂ --R₁ --NH₂ in which R₁ is a C₂ -C₆ linear or branched alkylene groupor an o-phenylene group;

or a group of formula ##STR3## in which n=2, 3, 4, 5 m=0, 1,

and I=0, 1;

X represents a bridging ligand between the two platinums selected amongCl, Br, F and I;

the dissociable Ld group represents:

either two monodentate B ligands selected among NO₃ or R COOH, in whichR is a gluconic or glucoronic acid residue;

or the bidentate B--B ligand selected among ##STR4## in which R ishydrogen, the methyl, ethyl, phenyl, benzyl group; Hal is a halogen atomselected among Cl, Br, F and I.

A family of preferred compounds of the invention are the compounds offormula (I) or (II) in which:

Y--Y represents a bidentate ligand selected among ethylenediamine,o-phenylenediamine, trimethylenediamine, 1,2-cyclohexanediamine and2-(aminomethyl) cyclohexylamine;

X is Cl;

A₁ and A₂ represent either two ammino monodentate ligands or they arebonded together and form a bidentate ligand selected amongethylenediamine, o-phenylenediamine, trimethylenediamine,1,2-cyclohexanediamine and 2-(aminomethyl) cyclohexylamine;

Ld is:

either two monodentate B ligands selected among NO₃ or RCOOH, in which Ris a gluconic or glucoronic acid residue;

or a bidentate B--B ligand selected among dicarboxylate, SO₄, oxalate,malonate, 1,1-cyclobutanedicarboxylate;

Hal is Cl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an infrared spectrum of the platinum complex: [(cis-diammine)(1R),(2R)- diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate;

FIG. 2 is an infrared spectrum of the platinum complex: [(cis-diammine)(1S),(2S)- diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate;

FIG. 3 is an infrared spectrum of the platinum complex: [(cis-diammine)(R),(S)- diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate;

FIG. 4 is an infrared spectrum of the platinum complex: [bis(cis-diammine)-μ- dichloro-di-Pt(II)] 1,1-cyclobutanedicarboxylate; and

FIG. 5 is an infrared spectrum of the platinum complex: [(cis-diammine)(trans- dichloro)(1R),(2R)-diaminocyclohexane-μ-dichloro-di-Pt(II)-Pt(IV)] oxalate.

The invention also relates to a process for the preparation of the newdinuclear platinum complexes, characterized in that said processconsists in reacting in an aqueous solution and in equimolar proportiontwo mononuclear platinum complexes, one of which is a di-halogenatedplatinum complex C1 and the other a platinum complex C2 comprisingeither two monodentate B ligands or one bidentate B--B ligand as definedabove, such that a bridge forms ##STR5## between the two complexes, inwhich X is as defined above.

According to a preferred embodiment of the invention, the processconsists in:

a) dissolving in distilled water a mononuclear platinum complex C1 byheating in a water-bath;

b) dissolving like in step a) the mononuclear platinum complex C2 indistilled water;

c) mixing the two solutions and boiling the reaction mixture at 80° C.;

d) leaving the reaction mixture at room temperature; and

e) filtering, washing the needle- or feather-shaped pale yellowcrystalline precipitate resulting from step d) with warm water and thenwith alcohol;

In step d), the alcohol used is advantageously ethanol.

The examples of mononuclear complexes C1 and C2 are the followingmononuclear platinum complexes:

Complexes C1

the cisplatin [Pt(II)-cis Cl₂ (NH₃)₂ ], hereafter "DDP",

the complex [Pt(II)-Cl₂ (1S),(2S)-diaminocyclohexane], hereafter "d-DCdach",

the complex [Pt(II)-Cl₂ (1R),(2R)-diaminocyclohexane], hereafter "I-DCdach",

the complex [Pt(II)-Cl₂ (1R),(2S)-diaminocyclohexane], hereafter "cis-DCdach",

the complex [Pt(IV)-oxalato trans Cl₂ (1R),(2R)-diaminocyclohexane ],hereafter "I-OHP.Cl".

Complexes C2

the oxaliplatin: [Pt(II)-oxalato (1R),(2R)-diaminocyclohexane],hereafter "I-OHP",

the complex [Pt(II)-oxalato (1R),(1S)-diaminocyclohexane], hereafter"cis-OHP",

the complex [Pt(II)-(NO₃)₂ (1R),(2R)-diaminocyclohexane], hereafter"I-DN dach",

the complex [Pt(II)-(NO₃)₂ (1S),(2S)-diaminocyclohexane], hereafter"d-DN dach",

the complex [Pt(II)-(NO₃)₂ (1R),(2S)-diaminocyclohexane], hereafter"cis-DN dach",

the carboplatin [Pt(II)-cis-diammine 1,1-cyclobutanedicarboxylate],hereafter "CBDCA",

the complex [Pt(IV)-oxalato trans Cl₂ (1R),(2R)-diaminocyclohexane ],hereafter "I-OHP.Cl".

The mononuclear platinum complexes C1 and C2 are advantageouslyoxaliplatin and cisplatin.

The compounds of the present invention of formula (I) are activeprinciples of pharmaceutical compositions whose toxicity is compatiblewith their use as medicaments.

Thus, according to another aspect thereof, the present invention relatesto pharmaceutical compositions containing a dinuclear platinum complexof formula (I) or (II) as the active principle.

The compounds of the present invention are administered in unit dosageform. The unit dosage forms are formulated in pharmaceuticalcompositions in which the active principle is mixed with apharmaceutical vehicle.

The pharmaceutical compositions containing the dinuclear platinumcomplex of the invention, as the active principle, may be administeredorally or parenterally (intramuscularly or intravenously).

For oral administration, the pharmaceutical compositions may be in theform of tablets, gelatin capsules, powders, granules or any other formwhich may be administered orally. The pharmaceutical compositions mayfurther contain pharmaceutically acceptable vehicles that are compatiblewith the compounds of the invention.

The pharmaceutical compositions are preferably administered parenterally(intramuscularly--intravenously). The injectable solutions are aqueoussolutions containing at least a pharmaceutically acceptable acid bufferfree from any chloride ions and a neutral substance for the vehicle.

Preferably, the pH of the injectable solution is adjusted to a valuecomprised preferably between 6.8 and 7.

According to the invention, inorganic or organic acids and theirpharmaceutically acceptable alkaline salts, free from any chloride ions,are advantageously used, as the acid buffer.

More particularly, an acid or a mixture of pharmaceutically acceptablecorresponding organic acids and alkaline salts are used. As the organicacid, a dicarboxylic amino acid, such as aspartic or glutamic acid ispreferably used and as the alkaline salt, a corresponding lithium,sodium or potassium salt is used. As the inorganic acid, acetic acid orphosphoric acid may be used, for example.

As the preferential acid buffer, the glutamic acid is used in thepresence or absence of sodium glutamate.

According to the invention, the composition further generally comprisesa neutral substance acting as the vehicle, such as a carbohydrate likethe lactose, glucose, mannitol or sorbitol or similar compounds.

Said solution may thus be administered parenterally, if necessary,together with other cytostatic agents which are physico-chemicallycompatible with the dinuclear platinum complexes of the invention and inaccordance with the current practices of anticancerous therapy.

The compounds of the present invention have an antitumor activityagainst experimental tumors in rats, such as L 1210 and are thusparticularly useful in tumor chemotherapy.

According to another one of its aspects, the present invention relatesto the use of the products of formula (I) for the preparation ofmedicaments intended to treat various cancers.

PHARMACOLOGICAL STUDY: ANTITUMOR ACTIVITY

The antitumor activity of the compounds of the invention wasdemonstrated by the following test.

EXPERIMENT

10⁵ leukemia cells L 1210 of mice in a saline suspension were injectedintraperitoneally to groups of 6 mice CDF1 on day 0. The compound to betested was administered intraperitoneally 1, 3 and 5 days aftertransplanting cancerous cells.

Control groups of 6 mice were also constituted but were not administeredwith the compounds to be tested.

The therapeutical effectiveness of the compounds of the invention wasmeasured by the ratio T/C %. This ratio represents 100 times the averagesurvival time of the group administered with the compound to be testeddivided by the average survival time of the control group which was notadministered with the compound to be tested.

The results are shown in tables 1 and 2 below:

                  TABLE 1                                                         ______________________________________                                        Antitumor activity of the complex of the invention: the dinuclear             platinum complex of oxaliplatin and of cisplatin (I-OHP.DDP) compared         with the activity of the compounds of the prior art: cisplatin (DDP),         oxaliplatin (I-OHP) and oxaliplatin/cisplatin (I-OHP + DDP) combination       against cancerous cells L 1210.                                                         T/C (%)                                                                       Dose (mg/kg)                                                                  12,5   6,25       3,12     1,56                                     ______________________________________                                        DDP         78       245        226    124                                    I-OHP       308 (4/6)                                                                              253 (1/6)  211 (1/6)                                                                            158                                    I-OHP + DDP          230 (1/6)  284 (2/6)                                                                            167                                    (1:1)                                                                         I-OHP · DDP                                                                      234 (1/6)                                                                              347 (3/6)  378 (5/6)                                                                            183                                    ______________________________________                                         The numbers in brackets represent the number of mice cured in a group of      mice.                                                                    

                  TABLE 2                                                         ______________________________________                                        Antitumor activity of the complex of the invention (I-OHP.DDP)                compared with the activity of the known combination I-OHP + DDP               against cancerous ceils L 1210 which have been treated with DDP               beforehand.                                                                            T/C (%)                                                                       Dose (mg/kg)                                                                  6.25      3.12     1,56                                              ______________________________________                                        I-OHP + DDP                                                                              105         113      103                                           I-OHP · DDP                                                                     207 (2/6)   398 (5/6)                                                                              345 (6/6)                                     ______________________________________                                         The numbers in brackets represent the number of mice cured in a group of      mice.                                                                    

The results collated in tables 1 and 2 show the effectiveness of thedinuclear platinum complex of the invention as an antitumor agent.Indeed, at an effective dose of 3.12 mg/kg, the complex of the inventionenabled 5 mice out of 6 to recover against 2 out of 6 for theoxaliplatin/cisplatin combination and 1 out of 6 for the oxaliplatin(Table 1), it being understood that a lesser dose is not sufficient andthat a greater dose is toxic.

Furthermore, it is noted that the leukemia cells L 1210 are previouslytreated with cisplatin, the complex of the invention is very effectiveat a dose of 1.56 mg/kg: 6 mice out of 6 have recovered whereas theknown combination is not at all effective (table 2).

STABILITY

Moreover, the stability of the dinuclear platinum complexes of theinvention was checked by paper chromatography.

The stability was indeed assessed by the values of the characteristicRf: ##EQU1## Rf is obtained by paper chromatography (filter paper Toyo2×20 cm) at room temperature using some SnCl₂ as the detector.

The results are shown in Table 3 below:

The products of the invention are identified below by a code number NCUwhich is attributed by the inventors.

                  TABLE 3                                                         ______________________________________                                                        Rf                                                                            Eluant solvant                                                NCU    Complexes      20% Methanol                                                                             20% Ethanol                                  ______________________________________                                        501    I-OHP · DDP                                                                         0,64       0,55                                         --     I-OHP · DDP*                                                                        0,64       0,55                                         502    d-OHP · DDP                                                                         0,62       0,52                                         503    cis-OHP · DDP                                                                       0,72       0,70                                         504    I-OHP · I-DC dach                                                                   0,68       0,38                                         507    DDP · I-DN dac                                                                      0,69       0,64                                         510    L-DN dach · l-DC dach                                                               --         0,72                                         513    DDP · CBDCA                                                                         0,69       0,59                                         514    I-OHP · CI · DDP                                                           0,73       0,73                                         --     DDP            0,80       0,57                                         --     I-OHP          0,65       0,63                                         --     d-OHP          0,67       0,60                                         --     cis-OHP        0,70       0,65                                         --     CBDCA          0,76       0,74                                         --     PtCl.sub.2 (l-dach)                                                                          --         0,74                                         --     Pt(NO.sub.3).sub.2 (l-dach)                                                                  --         0,13                                         ______________________________________                                         *the compound labelled with this asterisk has undergone heating in some       HCl 1N                                                                   

The invention shall now be illustrated more precisely by the followingillustrating and non-limiting examples:

EXAMPLE 1

Synthesis of a dinuclear platinum complex of I-OHP and cisplatin:[(cis-diammine) (1R),(2R)-diaminocyclohexane-μ-dichloro-di-Pt(II)]oxalate or else [(NH₃)₂ Pt (μ-Cl)₂ Pt (trans-I-dach)] ox, hereafterI-OHP.DDP: NCU 501 of chemical structure: ##STR6##

0.60 g (2 mmol) of cisplatin (molar mass=299 g/mol) is dissolved in 90ml of distilled water by heating in a water-bath (pH≈5.0). 0.80 g (2mmol) of I-OHP (molar mass=397 g/mol) is dissolved in 80 ml of distilledwater by heating in a water-bath (pH≈5.0). Both solutions are combinedand then the reaction mixture is boiled to 80° C. After 15-30 minutes, aneedle-shaped pale yellow precipitate is obtained. The precipitate isfiltered, washed with warm water and then with alcohol. 0.61 g of thepale yellow crystalline complex is thus obtained with a yield of 87%.

The infrared absorption spectrum of this complex is represented in FIG.1.

    ______________________________________                                        Elemental analysis: C.sub.8 H.sub.20 N.sub.4 O.sub.4 Pt.sub.2 Cl.sub.2        (molar mass = 697 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             13,77%   13,98%                                                 H              2,86%    3,08%                                                 N              8,03%    8,06%                                                  Pt           55,95%   52,9%                                                  ______________________________________                                    

EXAMPLE 2

Synthesis of a dinuclear platinum complex of d-OHP and cisplatin:[(cis-diammine) (1S), (2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)]oxalate or else [(NH₃)₂ Pt (μ-Cl)₂ Pt (trans-d-dach)] Ox, hereafterd-OHP.DDP: NCU 502.

0.60 g (2 mmol) of cisplatin is dissolved in 90 ml of distilled water byheating in a water-bath (pH≈5.0). 0.80 g (2 mmol) of d-OHP is alsodissolved in 80 ml of distilled water by heating in a water-bath(pH≈5.0). Both solutions are combined and then the reaction mixture isboiled at 80° C. After 15-30 minutes, a needle-shaped pale yellowprecipitate is obtained. The precipitate is filtered, washed with warmwater and then with alcohol. 0.60 g of the expected pale yellowcrystalline complex is thus obtained with a yield of 86%.

The infrared absorption spectrum is represented in FIG. 2.

    ______________________________________                                        Elemental analysis: C.sub.8 H.sub.20 N.sub.4 O.sub.4 Pt.sub.2 Cl.sub.2        (molar mass = 697 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             13,77%   13,60%                                                 H              2,86%    2,96%                                                 N              8,03%    8,09%                                                  Pt           55,95%   --                                                     ______________________________________                                    

EXAMPLE 3

Synthesis of a dinuclear platinum complex of cis-OHP and of cisplatin:[(cis-diammine) (R),(S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalateor else [(NH₃)₂ Pt (μ-Cl)₂ Pt (cis-dach)] Ox, hereafter cis-OHP.DDP: NCU503.

0.60 g (2 mmol) of cisplatin is dissolved in 90 ml of distilled water byheating in a water-bath (pH≈5.0). 0.80 g (2 mmol) of cis-OHP is alsodissolved in 80 ml of distilled water by heating in a water-bath(pH≈5.0). Both solutions are combined and then again heated for onehour. After concentrating the solution at 1/3-1/2 of its initial volumeand leaving the mixture at room temperature, needle-shaped pale yellowcrystals are obtained. The crystals are filtered, washed with warm waterand then with alcohol. 0.61 g of the expected needle-shaped pale yellowcrystalline complex is thus obtained with a yield of 87%.

The infrared absorption spectrum is represented in FIG. 3.

    ______________________________________                                        Elemental analysis: C.sub.8 H.sub.20 N.sub.4 O.sub.4 Pt.sub.2 Cl.sub.2        (molar mass = 696 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             13,77%   13,78%                                                 H              2,86%    2,90%                                                 N              8,03%    8,03%                                                  Pt           55,95%   --                                                     ______________________________________                                    

EXAMPLE 4

Synthesis of a dinuclear platinum complex of I-OHP and of I-DC dach:[bis(1R),(2R)-diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate or else[(trans-I-dach) Pt (μ-Cl)₂ Pt (trans-I-dach)] Ox, hereafter I-OHP.DCdach: NCU 504.

0.40 g (1 mmol) of I-OHP is dissolved in 40 ml of distilled water byheating in a water-bath. 0.38 g (1 mmol) of I-DC dach (molar mass=379g/mol) is also dissolved in 300 ml of distilled water by heating in awater-bath. Both solutions are combined and then the reaction mixture isboiled for 1 hour. After the reaction mixture has been left to rest atroom temperature, needle-shaped pale yellow crystals are obtained. Afterfiltration, the crystals are washed with warm water and then withalcohol. 0.30 g of the expected needle-shaped pale yellow crystallinecomplex is thus obtained with a yield of 39%.

    ______________________________________                                        Elemental analysis: C.sub.14 H.sub.28 N.sub.4 O.sub.4 Pt.sub.2 Cl.sub.2       (molar mass = 777 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             21,62%   20,82%                                                 H              3,60%    3,84%                                                 N              7,20%    7,38%                                                  Pt           50,19%   --                                                     ______________________________________                                    

EXAMPLE 5

Synthesis of a dinuclear platinum complex of I-OHP and of d-DC dach:[(1R), (2R)-diaminocyclohexane(1S),(2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate or else[(trans-I-dach) Pt (μ-Cl)₂ Pt (trans-d-dach)] Ox, hereafter I-OHP.d-DCdach: NCU 505.

0.40 g (1 mmol) of I-OHP is dissolved in 40 ml of distilled water byheating in a water-bath and 0.38 g (1 mmol) of d-DC dach (molar mass=379g/mol) is similarly dissolved in 300 ml of distilled water. Bothsolutions are combined and then the reaction mixture is boiled for 1hour. After the reaction mixture has been left to rest at roomtemperature, needle-shaped pale yellow crystals are obtained. Afterfiltration, the crystals are washed with warm water and then withalcohol. 0.30 g of the crystalline complex is thus obtained with a yieldof 39%.

    ______________________________________                                        Elemental analysis: C.sub.14 H.sub.28 N.sub.4 O.sub.4 Pt.sub.2 Cl.sub.2       (molar mass = 777 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             21,62%   21,52%                                                 H             3,60%    3,99%                                                  N             7,20%    7,05%                                                   Pt           50,19%   --                                                     ______________________________________                                    

EXAMPLE 6

Synthesis of a dinuclear platinum complex of I-OHP and of cis-DC dach:[(1R),(2R)-diaminocyclohexane(R),(S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate or else[(trans-I-dach) Pt (μ-Cl)₂ Pt (cis-dach)] Ox, hereafter I-OHP.cis DCdach: NCU 506.

0.40 g (1 mmol) of I-OHP is dissolved in 40 ml of distilled water byheating in a water-bath. 0.38 g (1 mmol) of cis-DC dach (molar mass=379g/mol) is similarly dissolved in 300 ml of distilled water. Bothsolutions are combined and then the reaction mixture is boiled forapproximately 1 hour. After the reaction mixture has been left to restat room temperature, needle-shaped pale yellow crystals are obtained.The precipitate is filtered, washed with warm water and then withalcohol. 0.28 g of the expected needle-shaped yellow crystalline complexis thus obtained with a yield of 36%.

    ______________________________________                                        Elemental analysis: C.sub.14 H.sub.28 N.sub.4 O.sub.4 Pt.sub.2 Cl.sub.2       (molar mass = 777 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             21,62%   20,91%                                                 H             3,60%    3,55%                                                  N             7,20%    7,05%                                                   Pt           50,19%   --                                                     ______________________________________                                    

EXAMPLE 7

Synthesis of a dinuclear platinum complex of cisplatin and of I-DN dach:[(cis-diammine) (1R),(2R)-diaminocyclo-hexane-μ-dichloro-di-Pt(II)]Nitrate or else [(NH₃)₂ Pt (μ-Cl)₂ Pt(trans-I-dach)] (NO₃)₂, hereafterDDP.I-DN dach: NCU 507.

0.299 g (1 mmol) of cisplatin is dissolved in 50 ml of distilled waterby heating in a water-bath ((pH about 5.0). 0.433 g (1 mmol) of I-DNdach (molar mass=433 g/mol) is similarly dissolved in 20 ml of distilledwater. Both solutions are combined and then the reaction mixture isboiled. After approximately 30 minutes, a feather-shaped very paleyellow crystalline precipitate is obtained. The precipitate is filtered,washed with warm water and then with alcohol. 0.30 g of the expectedcrystalline complex is thus obtained with a yield of 36%.

    ______________________________________                                        Elemental analysis: C.sub.6 H.sub.20 N.sub.6 O.sub.6 Pt.sub.2 Cl.sub.2        (molar mass = 829 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             20,26%   19,75%                                                 H              2,41%    2,78%                                                 N             10,13%   10,29%                                                  Pt           47,04%   --                                                     ______________________________________                                    

EXAMPLE 8

Synthesis of a dinuclear platinum complex of cisplatin and of d-DN dach:[(cis-diammine) (1S),(2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)]Nitrate or else [(NH₃)₂ Pt (μ-Cl)₂ Pt(trans-d-dach)] (NO₃)₂, hereafterDDP.d-DN dach: NCU 508.

0.299 g (1 mmol) of cisplatin is dissolved in 50 ml of distilled waterby heating in a water-bath ((pH about 5.0). 0.433 g (1 mmol) of d-DNdach (molar mass=433 g/mol) is similarly dissolved in 20 ml of distilledwater. Both solutions are combined and then the reaction mixture isboiled. After approximately 30 minutes, a feather-shaped very paleyellow crystalline precipitate is obtained. The precipitate is filtered,washed with warm water and then with alcohol. 0.28 g of the expectedcrystalline complex is thus obtained with a yield of 34%.

    ______________________________________                                        Elemental analysis: C.sub.6 H.sub.20 N.sub.6 O.sub.6 Pt.sub.2 Cl.sub.2        (molar mass = 829 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             20,26%   20,16%                                                 H              2,41%    2,31%                                                 N             10,13%   10,03%                                                  Pt           47,04%   --                                                     ______________________________________                                    

EXAMPLE 9

Synthesis of a dinuclear platinum complex of cisplatin and of cis-DNdach: [(cis-diammine) (R),(S)-diaminocyclo-hexane-μ-dichloro-di-Pt(l)]Nitrate or else [(NH₃)₂ Pt (μ-Cl)₂ Pt(cis-dach)] (NO₃)₂, hereafterDDP.cis-DN dach: NCU 509.

0.299 g (1 mmol) of cisplatin is dissolved in 50 ml of distilled waterby heating in a water-bath ((pH about 5.0). 0.433 g (1 mmol) of cis-DNdach (molar mass=433 g/mol) is similarly dissolved in 20 ml of distilledwater. Both solutions are combined and then the reaction mixture isboiled. After approximately 30 minutes, a feather-shaped very paleyellow crystalline precipitate is obtained. The precipitate is filtered,washed with warm water and then with alcohol. 0.28 g of the expectedcrystalline complex is thus obtained with a yield of 34%.

    ______________________________________                                        Elemental analysis: C.sub.6 H.sub.20 N.sub.6 O.sub.6 Pt.sub.2 Cl.sub.2        (molar mass = 829 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             20,26%   20,05%                                                 H              2,41%    2,25%                                                 N             10,13%   10,01%                                                  Pt           47,04%   --                                                     ______________________________________                                    

EXAMPLE 10

Synthesis of a dinuclear platinum complex of I-DC dach and of I-DN dach:[bis(1R), (2R)-diaminocyclohexane-μ-dichloro-10 di-Pt(II)] Nitrate orelse [(trans-I-dach) Pt (μ-Cl)₂ Pt(trans-I-dach)] (NO₃)2], hereafterI-DC dach.I-DN dach: NCU 510.

0.38 g (1 mmol) of I-DC dach is dissolved in 300 ml of distilled waterby heating in a water-bath ((pH about 5.0). 0.433 g (1 mmol) of I-DNdach (molar mass=433 g/mol) is similarly dissolved in 20 ml of distilledwater. Both solutions are combined and then the reaction mixture isboiled. After approximately 30 minutes, a feather-shaped very paleyellow crystalline precipitate is obtained. The crystals are filtered,washed with warm water and then with alcohol. 0.20 g of the expectedcrystalline complex is thus obtained with a yield of 25%.

    ______________________________________                                        Elemental analysis: C.sub.12 H.sub.28 N.sub.6 O.sub.6 Pt.sub.2 Cl.sub.2       (molar mass = 813 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             17,71%   18,05%                                                 H              3,44%    3,40%                                                 N             10,33%    9,79%                                                  Pt           47,37%   --                                                     ______________________________________                                    

EXAMPLE 11

Synthesis of a dinuclear platinum complex of d-DC dach and of I-DN dach:[(1R),(2R)-diaminocyclohexane(1S),(2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] Nitrate or else

[(trans-I-dach) Pt (μ-Cl)₂ Pt(trans-d-dach)] (NO₃)2], hereafter d-DCdach.I-DN dach: NCU 511.

0.38 g (1 mmol) of d-DC dach is dissolved in 300 ml of distilled waterby heating in a water-bath (pH about 5.0). 0.433 g (1 mmol) of I-DN dach(molar mass=433 g/mol) is similarly dissolved in 20 ml of distilledwater. Both solutions are combined and then the reaction mixture isboiled. After approximately 30 minutes, a feather-shaped very paleyellow crystalline precipitate is obtained. These crystals are filtered,washed with warm water and then with alcohol. 0.20 g of the expectedcrystalline complex is thus obtained with a yield of 25%.

    ______________________________________                                        Elemental analysis: C.sub.12 H.sub.28 N.sub.6 O.sub.6 Pt.sub.2 Cl.sub.2       (molar mass = 813 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             17,71%   17,65%                                                 H              3,44%    3,34%                                                 N              10,133% 10,30%                                                  Pt           47,97%   --                                                     ______________________________________                                    

EXAMPLE 12

Synthesis of a dinuclear platinum complex of cis-DC dach and of I-DNdach: [(1R),(2R)-diaminocyclohexane(R),(S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] Nitrate or else[(trans-I-dach) Pt (μ-Cl)₂ Pt(cis-dach)] (NO₃)₂ ], hereafter cis-DCdach.I-DN dach: NCU 512.

0.38 g (1 mmol) of cis-DC dach is dissolved in 300 ml of distilled waterby heating in a water-bath ((pH about 5.0). 0.433 g (1 mmol) of I-DNdach (molar mass=433 g/mol) is similarly dissolved in 20 ml of distilledwater. Both solutions are combined and then the reaction mixture isboiled for 30 minutes. After the solution has been concentrated at 50%of its initial volume, the mixture is left to rest at room temperature.A needle-shaped very pale yellow crystalline precipitate is obtained.These crystals are filtered, washed with warm water and then withalcohol. 0.15 g of the expected crystalline complex is thus obtainedwith a yield of 18%.

    ______________________________________                                        Elemental analysis: C.sub.12 H.sub.28 N.sub.6 O.sub.6 Pt.sub.2 Cl.sub.2       (molar mass = 813 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             17,71%   18,01%                                                 H              3,44%    3,45%                                                 N             10,33%   10,23%                                                  Pt           47,97%   --                                                     ______________________________________                                    

EXAMPLE 13

Synthesis of a dinuclear.platinum complex of DDP and CBDCA: [bis(cis-diammine)-μ-dichloro-di-Pt(II)] 1,1-cyclobutanedicarboxylate, orelse [(NH₃)₂ Pt (μ-Cl)₂ Pt(NH₃)₂ ] CBDCA, hereafter DDP.CBDCA: NCU 513.

0.30 g (1 mmol) of DDP is dissolved in 50 ml of distilled water byboiling. 0.37 g (1 mmol) of CBDCA and a drop of HCl 1N are then added tothe reacture medium and the mixture is boiled again for 30 minutes.After approximately 30 minutes, needle-shaped yellowish brown crystalsare obtained. These crystals are filtered, washed with hot water andthen with alcohol. 0.50 g of the expected crystalline complex is thusobtained with a yield of 75%.

The infrared absorption spectrum is represented in FIG. 4.

    ______________________________________                                        Elemental analysis: C.sub.6 H.sub.12 N.sub.4 O.sub.4 Pt.sub.2 Cl.sub.2        (molar mass = 671 g/mol).                                                                 Calculated                                                                           Found                                                      ______________________________________                                        C             10,73%   10,18%                                                 H              2,68%   2,14%                                                  N              8,34%   8,33%                                                   Pt           58,12%   --                                                     ______________________________________                                    

EXAMPLE 14

Synthesis of a dinuclear platinum complex of I-OHP.Cl and of DDP:[(cis-diammine) (trans-dichloro)(1R),(2R)-diaminocyclohexane-μ-dichloro-Pt(II)-Pt(IV)] Oxalate or else[(NH₃)₂ Pt (II) (μ-Cl)₂ Pt(IV) (trans-Cl₂ -trans-I-dach)] Ox, hereafterI-OHP.Cl-DDP: NCU 514.

0.47 g (1 mmol) of I-OHP.Cl (molar mass=469 g/mol) is dissolved in 50 mlof distilled water by heating in a water-bath and 0.3 g (1 mmol) of DDP(molar mass=299 g/mol) is similarly dissolved in 30 ml of distilledwater. Both solutions are combined and then the reaction mixture isboiled for 30 minutes. When the reaction is completed, very pale yellowcrystalline precipitates are obtained. The precipitates are filtered,washed with warm water and then with alcohol. 0.33 g of the expectedcrystalline complex is thus obtained with a yield of 50%.

The infrared absorption spectrum is represented in FIG. 5.

    ______________________________________                                        Elemental analysis: C.sub.8 H.sub.20 N.sub.4 O.sub.4 Cl.sub.4 Pt.sub.2        (molar mass = 768                                                             g/mol).                                                                                   Calculated                                                                           Found                                                      ______________________________________                                        C             12,53%   12,50%                                                 H              2,61%    2,75%                                                 N              7,29%    7,40%                                                  Pt           50,78%   --                                                     ______________________________________                                    

We claim:
 1. A compound of formula (I) or (II): ##STR7## wherein: Y--Yis an amine bidentate ligand of the formula:NH₂ --R₁ NH₂ in which R₁ isa C₂ -C₆ linear or branched alkylene group or an o-phenylene group; oror a group of the formula: ##STR8## wherein n=2, 3, 4 or 5; m=0 or 1 and1=0 or 1; A₁ and A₂ represent either two identical ammine monodentateligands, n-isopropylamine or (C₃ -C₇) cycloalkylamine or they are bondedtogether thereby forming an amine bidentate ligand of the formula: NH₂--R₁ --NH₂ in which R₁ is a C₂ -C₆ linear or branched alkylene group oran o-phenylene group; or a group of the formula: ##STR9## wherein n=2,3, 4or 5; m=0 or 1 and 1=0 or 1; X represents a bridging ligand linkingthe two platinum atoms selected from the group consisting of Cl, Br, Fand I; the dissociable Ld group represents: either two monodentate Bligands selected from the group consisting of NO₃ ⁻, gluconate andglucuronate; or the bidentate B--B ligand selected from the groupconsisting of: ##STR10## wherein R is hydrogen, methyl, ethyl, phenyl orbenzyl; and Hal is a halogen atom selected from the group consisting ofCl, Br, F and I.
 2. The compound of formula (I) or (II) according toclaim 8, wherein:Y--Y represents a bidentate ligand selected from thegroup consisting of ethylene diamine, o-phenylenediamine,trimethylenediamine, 1,2-cyclohexanediamine and2-(aminomethyl)cyclohexylamine; X is Cl; A₁ and A₂ represent either twoammine monodentate ligands or they are bonded together thereby forming abidentate ligand selected from the group consisting of ethylenediamine,o-phenylenediamine, trimethylenediamine, 1,2-cyclohexanediamine and2-(aminomethyl)cyclohexylamine; Ld is:either two monodentate B ligandsselected from the group consisting of NO₃ ⁻, gluconate and glucuronate;or the bidentate ligand B--B selected from the group consisting ofdicarboxylate, sulfate, oxolate, malonate and1,1-cyclobutanedicarboxylate; and Hal is Cl.
 3. The compound of formula(I) or (II) according to claim 1, wherein said compound is selected fromthe group consistingof:[(cis-diammine)(1R),(2R)-diaminocyclohexane-μ-dichloro-di-Pt(II)]oxalate,[(cis-diammine)(1S),(2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)]oxalate,[(cis-diammine)(1R),(1S)-diaminocyclohexane-μ-dichloro-di-Pt(II)]oxalate, [bis(1R),(2R)-diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate,[(1R),(2R)-diaminocyclohexane(1S),(2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate,[(1R),(2R)-diaminocyclohexane(R),(S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] oxalate [(cis-diammine)(1R),(2R)-diaminocyclohexane-μ-dichloro-di-Pt(II)] nitrate,[(cis-diammine) (1S),(2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)]nitrate, [(cis-diammine)(1R),(1S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] nitrate, [bis(1R),(2R)-diaminocyclohexane-μ-dichloro-di-Pt(II)] nitrate,[(1R),(2R)-diaminocyclohexane(1S),(2S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] nitrate,[(1R),(2R)-diaminocyclohexane(1R),(1S)-diaminocyclohexane-μ-dichloro-di-Pt(II)] nitrate, [bis(cis-diammine)-μ-dichloro-di-Pt(II)] 1,1-cyclobutanedicarboxylate, and[(cis-diammine)(transdichloro-(1R),(2R)-diaminocyclohexane-μ-dichloro-Pt(II)-Pt(V)]oxalate.
 4. A process for the preparation of a compound of formula (I)or (II), consisting of:reacting, in an aqueous solution and in equimolarproportion, two mononuclear platinum complexes, one of which is adi-halogenated platinum complex C1 and the other a platinum complex C2comprising either two monodentate B ligands or one bidentate B--B ligandas defined in claim 1 such that a bridge of the structure: ##STR11##between the two complexes in which X is as defined in claim
 1. 5. Theprocess according to claim 4, which further consists of:a) dissolvingthe mononuclear platinum complex C1 in distilled water by theapplication of heat in a water-bath; b) dissolving, as in step a), themononuclear platinum complex C2 in distilled water; c) mixing the twosolutions and boiling the reaction mixture at 80° C.; d) allowing thereaction mixture to stand at room temperature; and e) filtering andwashing the needle- or scale-shaped pale yellow crystalline precipitatewhich forms in step d) with warm water and then with alcohol.
 6. Theprocess according to claim 5 complex C1 is selected from the groupconsisting of:[Pt(II)-cis Cl₂ (NH₃)₂ ] (cisplatin), [Pt(II)-Cl₂(1S),(2S)-diaminocyclohexane], [Pt(II)-Cl₂(1R),(2R)-diaminocyclohexane], [Pt(II)-Cl₂(1R),(2S)-diaminocyclohexane], and [Pt(IV)-oxalate trans Cl₂(1R),(2R)-diaminocyclohexane], and the complex C2 is selected from thegroup consisting of: [Pt(II)-oxalate (1R),(2R)-diaminocyclohexane](oxaliplatin), [Pt(II)-oxalate(1R),(1S)-diaminocyclohexane],[Pt(II)-(NO₃)₂ (1R),(2R)-diaminocyclohexane], [Pt(II)-(NO₃)₂(1S),(2S)-diaminocyclohexane], [Pt(II)-(NO₃)₂(1R),(2S)-diaminocyclohexane], [Pt(II)-cis-diammine1,1-cyclobutanedicarboxylate] (a carbo-platinum), and [Pt(IV)-oxalatetrans Cl₂ (1R),(2R)-diaminocyclohexane].
 7. A pharmaceutical compositioncontaining a compound according to any one of claims 1, 2 or 3 as theactive principle in combination with a pharmaceutically acceptablecarrier.